Fetal alcohol spectrum disorder (FASD) is one of the primary causes of intellectual disability in western nations, with neurobehavioral hallmarks such as deficits in learning, memory and mood. While it is known that developmental ethanol exposure can disrupt sleep structure, here we propose that developmental ethanol exposure may induce long-lasting disruption of neural activity patterns during sleep which are known to be important for memory consolidation and synaptic homeostasis. If so, this would create a situation wherein the normal ability of the nervous system to repair and readjust itself during sleep would be impaired, resulting in a daily insult to nervous system function long after the ethanol exposure ended. Specifically, in this proposal (PA- 12-177: Alcohol abuse, sleep disorders and circadian rhythms [R01]) we plan to explore the effects of binge- like ethanol exposure of prenatal or neonatal mice on long-term changes in sleep-associated activity in the olfacto-hippocampal pathway, and to begin to explore the role of GABAergic interneurons in this network activity. While prolonged exposure paradigms may align more closely to common etiologies of FASD, the binge model allows a more precise dissection of mechanisms, and thus potential avenues of treatment. Aim 1 is to test the hypothesis that early ethanol exposure induces long-term modification of both local (within region) and global (between regions) network activity within the olfacto-hippocampal pathway during slow-wave sleep. We will explore the long-lasting effects of early ethanol exposure on sleep related changes in single-unit activity and regional coherence, and predict specific disruptions in sleep structure, spike train temporal structure and in resting state functional connectivity during sleep that could result in cognitive and behavioral deficits. Aim 2 is to test the hypothesis that early ethanol exposure induces long-term modification of GABAergic interneuron structure and function in hippocampus and piriform cortex. We will explore the long-lasting effects of early ethanol exposure on GABAergic cell survival and, using a novel transgenic model, test whether disturbance in a specific GABAergic cell class known to be important for controlling neural synchrony mimics developmental ethanol's effects on neural circuit function in waking and sleep. Finally, Aim 3 will explore the hypothesis that neuroprotectants delivered at the time of the early ethanol exposure, or GABAergic or slow-wave sleep manipulations in adults can prevent or repair sleep disruption and its effects on cognition. If successful, the data could open a new window into both understanding and repair of early ethanol-induced neural and cognitive impairment. Furthermore, this collaborative proposal brings an established researcher in another field into the ethanol field (Wilson).